This application is a request for continued funding of 5RO1 AI033144 for Years 19-23 of a highly productive measles vaccine (MV) immunogenetics research program. Measles remains an epidemic virus in much of the world, leading to millions of infections and 164,000 deaths each year, and the current vaccine results in a failure rate of 2-10% after two doses. For 2011, the US has had 211 cases, more than in any year of the last decade. Our research is focused on identifying critical genetic determinates of immunity by examining associations between heterogeneity in humoral and cellular immune responses to MV and gene polymorphisms. Importantly, our research demonstrates that humoral and cellular immune responses to MV are significantly associated with HLA alleles and SNPs in candidate immune response genes, but these associations do not explain all of the variance in immune responses seen within the population. We will comprehensively identify the genetic determinants that explain our finding that the heritability of MV- induced humoral immunity is nearly 90%. To do so, we propose a state-of-the-art genome-wide association study (GWAS) design, followed by replication studies in independent cohorts, and finally validation studies to determine the functional consequences of replicated SNPs. The data from our study will support a new vaccinomics Discover-Replicate-Validate-Apply paradigm for new vaccine development by defining how variations in MV immune responses are determined by gene polymorphisms. To accomplish these goals, we propose the following Specific Aims: 1) Discover: To perform a GWAS to identify novel genetic associations between SNPs, multigenic interactions, and gene networks/pathways and markers of humoral (neutralizing antibody) and cell-mediated (IFN-g ELISPOT) immunity to MV, 2) Replicate: To replicate a prioritized set of the strongest associations from both our GWAS (Aim 1) and candidate gene SNPs from our currently funded grant in an independent, population-based cohort of subjects, and 3) Validate: To determine the direct effects and/or downstream functional consequences on immune outcomes of selected replicated genetic variants. This application is innovative and significant in that it will: examin the effect of gene polymorphisms on the heterogeneity of measles vaccine immune responses, provide data that may explain mechanisms for these variations in MV immune responses, and provide data to support a novel paradigm of Discover-Replicate- Validate-Apply for new vaccine development. These studies will provide specific knowledge for understanding measles immunity, as well as provide a model framework for estimating the genetic contribution to variations in immune responses to a viral vaccine. Lastly, our work may provide knowledge important to the development of new viral vaccines-particularly against measles-by understanding genetic restrictions that prevent protective immune responses to vaccine.